This project in clinical psychopharmacology has three long-term objectives: to understand the underlying cellular defect in manic-depressive illness; to understand the mechanism of Li+'s therapeutic effect in that illness; and to seek practical means, based on physiological understanding, of increasing the efficacy of Li+ therapy. Our methods include use of human erythrocyte (RBC) as an accessible, experimentally convenient model membrane system sharing many transport mechanisms with nerve and muscle; a recently developed technique for maintaining RBC for long periods in sterile culture and thereby gaining the ability to analyze slow effects of Li+ in vitro; an ultramicro technique of Li+ analysis at very low concentrations and in very small samples; and compartmental analysis of Li+ pharmacokinetic data to estimate Li+ levels and exchange at otherwise inaccessible sites in the human body. Three specific sets of experiments are proposed: 1. To identify the molecular mechanism by which, in vitro as well as in vivo, Li+ produces a slowly developing inhibition of Na+/Li+ countertransport in RBC. 2. Analogously, to identify the mechanisms whereby mania leads to raised choline levels in RBC, and whereby Li+ slowly causes a further rise in RBC choline. 3. To examine differences among manics, depressed patients, and normals in Li+ pharmacokinetics, and effects of Li+ therapy on these pharmacokinetics, especially as regards Li+ levels and exchange in muscle.